Prevention of UV-carcinogenesis through DNA methylation-dependent immunomodulation

 描述（由申请人提供）：美国每年诊断出约130万例非黑色素瘤皮肤癌新发病例，对公共卫生和医疗保健支出产生巨大影响。因此，迫切需要安全有效的化学预防策略。过度暴露于太阳紫外线（UV）辐射是一个主要的风险因素，紫外线诱导的免疫抑制在皮肤癌发生中起着关键作用。众所周知，紫外线照射诱导炎症介质，损害树突状细胞（DC）和效应T细胞的功能，并诱导抑制性T细胞。紫外线诱导的表观遗传修饰，如DNA超甲基化，似乎在皮肤的光损伤中起重要作用。现在出现的一种模型表明，表观遗传修饰，包括DNA超甲基化，是由UVB诱导的炎症介质，如环氧合酶-2（考克斯-2）/前列腺素E2诱导的，并作为炎症介质和受损DC功能之间的机制联系。我们已经证明，局部施用和厚朴，一种植物化学物质，从木兰植物，防止光致癌和UVB诱导的免疫抑制小鼠。我们的初步数据进一步表明，honokaline可以纠正或抑制DNA超甲基化在紫外线暴露的树突状细胞，这恢复树突状细胞介导的活动，包括刺激细胞。我们提出了一个创新的假设，即厚朴对UVB诱导的DNA高甲基化的抑制是其对UV诱导的免疫抑制的化学预防作用的关键。我们提出了三个相互关联的具体目标来测试在小鼠模型中的假设：（1）确定和厚朴酚诱导的抑制UV诱导的免疫抑制是否通过UV暴露皮肤中的DNA去甲基化发生，以及炎症介质是否在其中发挥作用;（2）确定和厚朴酚是否抑制UV诱导的耐受原性DC的发育，以及这是否是通过抑制DNA超甲基化介导的;和（3）确定和诺明对UV诱导的免疫抑制的抑制是否通过增强T细胞活化而发生，以及这是否通过抑制DNA超甲基化而介导。将使用多种方法的组合来验证结果，包括使用考克斯-2缺陷小鼠。创新：拟议的研究将：（1）确定局部或口服施用和厚朴的机制，以纠正UV诱导的免疫抑制并防止光致癌作用，从而为这种有前途的植物化学物质的进一步临床开发提供所需的数据;和（2）所产生的数据将提供关键的洞察机制，引发UVB-诱导DC中的DNA超甲基化，并确定这些机制的靶向是否足以防止UVB诱导的免疫抑制。影响：使用和厚朴开发新的早期干预策略可能有助于降低人类皮肤癌的风险，因为皮肤癌的风险是一个主要的公共卫生问题。

 DESCRIPTION (provided by applicant): The approximately 1.3 million new cases of nonmelanoma skin cancers diagnosed each year in the USA have a tremendous impact on public health and healthcare expenditures. Therefore, safe and effective chemopreventive strategies are urgently needed. Overexposure to solar ultraviolet (UV) radiation is a primary risk factor and that UV-induced immunosuppression plays a critical role in skin carcinogenesis. It is well established that UV irradiation induces inflammatory mediators, impairs the function of dendritic cells (DC) and effector T cells and induces suppressor T cells. UV-induced epigenetic modifications, such as DNA hypermethylation, seem to play an important role in photodamage of the skin. A model is now emerging that suggests that epigenetic modifications, including DNA hypermethylation, are induced by UVB-induced inflammatory mediators, such as cyclooxygenase-2 (COX-2)/prostaglandin E2, and act as a mechanistic link between the inflammatory mediators and compromised DC function. We have demonstrated that topical administration of honokiol, a phytochemical from the Magnolia plant, prevents both photocarcinogenesis and UVB-induced immunosuppression in mice. Our preliminary data further indicate that honokiol can correct or inhibit DNA hypermethylation in UV-exposed dendritic cells and that this restores dendritic cell-mediated activities including stimulation of cells. We propose to test the innovative hypothesis that inhibition of UVB-induced DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV- induced immunosuppression. We propose three inter-related Specific Aims to test the hypothesis in a mouse model: (1) Determine whether honokiol-induced inhibition of UV-induced immunosuppression occurs through DNA demethylation in UV-exposed skin and whether the inflammatory mediators play a role in this; (2) Determine whether honokiol inhibits the development of UV-induced tolerogenic DCs and whether this is mediated through inhibition of DNA hypermethylation; and (3) Determine whether honokiol inhibition of UV- induced immunosuppression occurs through enhancement of T cell activation and whether this is mediated through inhibition of DNA hypermethylation. A combination of approaches will be utilized to verify the results including the use of COX-2 deficient mice. Innovation: The proposed studies will: (1) Identify the mechanisms by which topical or oral administration of honokiol acts to correct UV-induced immunosuppression and prevent photocarcinogenesis, thereby providing data needed for further clinical development of this promising phytochemical; and (2) The data generated will provide critical insights into the mechanisms that elicit UVB- induced DNA hypermethylation in DC and establish whether targeting of these mechanisms is sufficient to prevent UVB-induced immunosuppression. Impact: The development of new early intervention strategies using honokiol may help to reduce the risk of skin cancer in humans, as the risk of skin cancer is a major public health concern.